Ovulation
Ovulation, the release of an oocyte from an ovary of a female animal, is an important step of female reproductive biology because it is required in order that the oocyte may be fertilized by male sperm.
In archetypical human females, ovulation takes place on approximately day 14 of the typically 28 day menstrual cycle. However, only approximately 10% of women regularly ovulate on day 14 of a 28 day cycle. The cycle length and day of ovulation within a single cycle can vary between women and, usually to a lesser extent, from time to time in a single woman. Variation in the cycle length of an individual woman includes both fluctuations from one cycle to the next and longer term “drifts” in cycle length which take place over several years and may be part of the ageing process.
In non-human mammals, the biology of ovulation varies considerably. Some animals, for example, dogs and cattle, conform approximately to the human model and exhibit a non-seasonal pattern of ovulation at regular intervals. Other animals (for example, sheep, rabbits, ferrets) require environmental cues, for example changing day length or the presence of males, in order for ovulation to be triggered. Other animals, for example mice, only ovulate in response to copulation. There are many circumstances, both in the fields of medicine and veterinary practice, where it is useful to know if ovulation has taken place.
In general terms, the ability to detect the presence or absence of ovulation is useful both in the diagnoses of disorders of ovulation and in providing information about likely fertility which can be used to choose suitable timing of sexual intercourse in order to increase or decrease the odds of pregnancy resulting in accordance with the wishes of the woman, in the field of human medicine, or in accordance with the wishes of the farmer or veterinarian in the field of animal husbandry. Furthermore, information about the timing of ovulation may be used to choose suitable timing of fertility treatments such as intrauterine insemination (IUI), artificial insemination or removal of ova for in vitro fertilisation.
It has been estimated that one in six human couples have an unwanted delay in conception (Taylor (2003) BMJ 327:434-436). Most of those couples do not have absolute infertility (that is, no chance of conception) but rather subfertility with a reduced chance of conception because of one or more factors in either or both partners.
As part of the diagnoses of subfertility one of the key questions which the clinician asks is ‘does the woman ovulate?’ In addition to answering the above question, knowing or predicting when the woman ovulates is also useful in cases of subfertility because it allows the couple and/or the physician involved in providing fertility enhancement treatment to time their sexual intercourse and/or therapeutic intervention so as to maximise the chances of conception.
Knowledge of the time of ovulation and thereby knowledge of a woman's fertility can also be useful where a woman in a sexual relationship wishes to avoid conception. By limiting unprotected sex to times when the woman is unlikely to be fertile, unwanted pregnancies can be avoided. Such a ‘natural’ method of contraception may be especially attractive to couples who have medical, religious or other reasons for avoiding the use of alternative contraception.
In the veterinary fields, animal sub-fertility may be a problem, particularly if the animals in question are commercially valuable (for example race horses, cattle, companion animals) or members of an endangered species. Additionally in many animal species stud fees and/or semen samples for artificial insemination are costly. There is therefore a need to limit those interventions to times when the female is fertile.
The Human Ovulatory Cycle
The cyclic changes in ovarian activity are controlled by the secretion of two hormones by the pituitary gland, follicle stimulating hormone (FSH) and luteinizing hormone (LH) under the control of the hypothalamus.
During the second half of the proceeding cycles, high levels of oestradiol (oestrogen) and progesterone (progestogen) act via the hypothalamus to suppress FSH and LH production by the pituitary gland. At the end of the proceeding cycle a decrease in production of oestradiol and progesterone by the corpus luteum removes suppression of the hypothalamus and FSH levels start to rise. Once a threshold is met, FSH stimulates a group of ovarian follicles into growth.
The dominant follicle continues to grow towards ovulation and as it does so it produces increasing amounts of oestradiol. This leads to a fall in FSH which removes support for non-dominant follicles and increases the dominant follicle's receptivity to LH. The high oestradiol level causes the pituitary gland to release a large surge of LH. This peak of LH triggers the rupture of the follicle and release of the oocyte (ovulation) approximately 37 hours after the beginning of the surge of LH or approximately 17 hours after its peak.
The remains of the ruptured follicle become the corpus luteum which produces progesterone which causes an abrupt change in the characteristics of the cervical mucus so as to make it impenetrable to sperm. A decrease in progesterone towards the end of the cycle causes the bleeding of menstruation.
Related changes in hormone levels are seen in veterinary species, the levels and timing of events altering from species to species—all result in a corresponding release of an ovum into the fallopian tube following rupture of a mature follicle.
By convention the human ovulatory cycle (also known as the menstrual cycle) considered to start from the first day of menses (day 1) and continue until the first day of menses of the following cycle takes place.
Detection of Ovulation
The UK Royal College of Obstetricians & Gynaecologists guidelines for investigating whether ovulation is likely to take place includes checking mid-luteal phase progesterone 7 days before expected menses. Other investigations which may be carried out include measuring LH, FSH and oestradiol concentrations in early follicular phase (days 2 to 6), (Taylor (2003) BMJ 327:494-497).
Measurement of hormone levels typically requires the drawing of a blood sample or the use of urine tests. These methods of measurement have the drawback that they require medical intervention and that each individual test costs money.
Urine tests additionally suffer from poor reliability because urine production rates are subject to unpredictable variations that lead to variations in hormone concentrations in the urine in the bladder.
Whilst blood tests may be highly suitable for occasional diagnostic testing, they have significant drawbacks if they are to be used for long periods of time. Several surrogate markers of ovulation in human female that are more suitable for home use and for sustained monitoring have been identified. The first of these involves the woman checking the consistency of her cervical mucus. The second involves the woman recording her body temperature. Body temperature is a widely used surrogate marker for the detection of ovulation. It is known that the LH peak which occurs just before ovulation causes a rise in body temperature, (see David M E & Fugo (1948), The cause of physiologic basal temperature changes in women Clin. Endocrinol. 8:550-563 and Coyne et al, (2000)) Circadian rhythm changes in core temperature over the menstrual cycle: method for non-invasive monitoring, A.L.C.J. Physiol. Regulatory Integrative Comp. Physiol. 279:1316-1320. The detection of that rise is used widely as a surrogate marker for ovulation.
The oestradiol rise before ovulation causes a slight and broad dip in body temperature before the LH-associated rise, (David & Fugo ibid) This dip is not currently used as a marker of ovulation because it is difficult to measure accurately, mainly because it is of low magnitude.
Temperature readings are typically taken once a day under the tongue with a standard mercury, spirit or electronic medical thermometer, although temperature may also be measured on the skin surface, under the armpit, in the ear or at any other suitable site. WO 03/078949 discloses a retrievable indwelling thermometer which may be used to measure rectal or intravaginal temperature over an extended period of time.
Current methods of taking and analysing temperature measurements in order to predict or detect ovulation have several drawbacks. Infrequently-taken temperatures may not be representative of the true basal body temperature and using a thermometer to take multiple temperatures manually is time consuming and inconvenient.
The device of WO 03/078949 may be used to take multiple temperature readings over a time period, but nevertheless the temperatures taken may be unrepresentative of the true basal body temperature for a number of reasons including the time-lag required for the temperature reading device to warm up after initial insertion, and non-relevant temperature changes which come about due to inadvertent or deliberate removal, urination and diurnal temperature variations. Such inaccuracies in temperature readings cause inaccuracies in the detection of the LH-associated temperature peak and prevent the detection of the oestradiol-associated temperature dip.
DE 3342251 speculates about a device for measuring the temperature in a female in order to detect temperature changes associated with ovulation. It is suggested that prediction of the timing of ovulation in the subsequent cycle may be earned out by counting forward in time from the start of the previously detected ovulatory cycle. The device disclosed in DE 3342251 measures multiple temperatures over at least part of several days. The specification does not disclose any real data (for example the data shown in the figure is obviously contrived). It is suggested that in order to minimise the effects of fluctuations in temperature that are irrelevant to detecting ovulation, maxima and/or minima curves be calculated and analysed for the presence of temperature changes indicative of ovulation. The Inventors of the present invention consider that the use of maxima or minima curves as disclosed in DE 3342251 is unlikely to work well because those variables are highly susceptible to irrelevant temperature changes (outlier data values).
GB 2077595 is directed mainly to monitoring the body temperatures of cows rather than humans. En fact page 3, column 1, lines 62 to 65 suggests that reliable detection of ovulation in humans by temperature measurement cannot be carried out. In terms of processing of temperature readings it is taught that temperature may be used for the detection of oestrus and for the detection of fever associated with poor health. It is also taught that a cow's temperature is partially dependent on ambient conditions and on individual characteristics of a particular cow. The recording of long term temperature readings in a cow is carried out in order to solve a different problem to that of detection of ovulation in humans. Whereas human women change temperature during their cycle, they exhibit similar temperatures from cycle to cycle. This is not the case in cattle. The reason for recording temperatures presented in GB 2077593 is in order to establish a temperature baseline for a single animal for a single cycle from which temperature changes associated with oestrus may be detected. The examples of GB 2077593 show a single reading being taken every day. The temperatures are measured electronically and transmitted by telemetry, but there is no disclosure of computer processing of the data. Presumably the farmer is presented with a set of data for his herd every day and makes his own assessment of them in order to determine which of his cows are in oestrus that day.
EP0424102 discloses a device which provides an indication of temperature and time of ovulation and of predicted periods of fertility. An algorithm for obtaining a steady reading is disclosed which would appear to be similar to that used in standard digital medical thermometers, but there is no disclosure of obtaining multiple temperature readings over an extended period and then discarding those that are spurious and those that are genuine but associated with events irrelevant to ovulation.
Systems and methods described herein may aid in (but are not limited to), the detection of ovulation (or the absence of ovulation) diagnosing infertility or subfertility; the prediction of ovulation as an aid to determining time periods of fertility in order to increase or decrease chances of conception; and the monitoring of medical interventions intended to assist conception in order to improve their success rates and/or reduce the risks of unwanted side effects.